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Intra-articular Xenotransplantation of Adipose-Derived Stromal Cells to Treat Osteoarthritis in a Goat Model

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Adipose-derived stromal cells (ASCs) have been investigated as a cell source for tissue regeneration. The purpose of this study was first to confirm if medial meniscectomy induces osteoarthritis (OA) in goats within a relative short period of time, and more importantly, to investigate if systemic treatment with immunosuppressive drugs is necessary in intra-articular ASC xenotransplantation for successful regeneration of articular cartilage and prevention of joint inflammation. Eight Korean native black goats 1–2 years of age underwent medial meniscectomy. To evaluate the gross and histological appearance of articular cartilage, knee joints were re-exposed by a medial parapatellar incision at 8 weeks. After macroscopic scoring of gross appearance, cartilage biopsy specimens 6 mm in diameter were obtained from the femoral condyle in four goats. The goats were injected with single intra-articular dose of 7×106 human ASCs (hASCs) 7 days after the second arthrotomy. Four animals were treated with daily injections of cyclosporin A 10 mg/kg for 7 days, followed by a reduced dose of 5 mg/kg for another 7 days, while other 4 animals did not receive immunosuppressive therapy. All animals were sacrificed for analysis 8 weeks after injection of hASCs. OA was successfully induced 8 weeks after medial meniscectomy. Eight weeks after injection of hASCs, various signs of articular cartilage regeneration were observed. There were no significant macroscopic and histological differences between goats treated with cyclosporine and untreated goats. Interleukin-1ß and tumor necrosis factor-α level from synovial fluid did not differ between cyclosporine-treated and untreated goats. The results indicate that immunosuppressive therapy did not influence the result of ASC xenotransplantation to treat OA.

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References

  1. Buckwalter JA, Mankin HJ, Grodzinsky AJ. Articular cartilage and osteoarthritis. Instr Course Lect. 2005;54:465–80.

    PubMed  Google Scholar 

  2. Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci. 2010;1192:230–7.

    Article  PubMed  CAS  Google Scholar 

  3. Derendorf H, Möllmann H, Grüner A, Haack D, Gyselby G. Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration. Clin Pharmacol Ther. 1986;39:313–7.

    Article  PubMed  CAS  Google Scholar 

  4. Friedman DM, Moore ME. The efficacy of intraarticular steroids in osteoarthritis: a double-blind study. J Rheumatol. 1980;7:850–6.

    PubMed  CAS  Google Scholar 

  5. Nerem R, Sage H, Kelley CA, McNicol LA. Symposium summary. Ann NY Acad Sci. 2002;961:386–91.

    Article  PubMed  Google Scholar 

  6. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889–95.

    Article  PubMed  CAS  Google Scholar 

  7. Benya PD, Padilla SR, Nimni ME. Independent regulation of collagen types by chondrocytes during the loss of differentiated function in culture. Cell. 1978;15:1313–21.

    Article  PubMed  CAS  Google Scholar 

  8. Lefebvre V, Peeters-Joris C, Vaes G. Production of collagens, collagenase and collagenase inhibitor during the dedifferentiation of articular chondrocytes by serial subcultures. Biochim Biophys Acta. 1990;1051:266–75.

    Article  PubMed  CAS  Google Scholar 

  9. Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect. 1998;47:487–504.

    PubMed  CAS  Google Scholar 

  10. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9:641–50.

    Article  PubMed  CAS  Google Scholar 

  11. Deasy BM, Jankowski RJ, Huard J. Muscle-derived stem cells: characterization and potential for cell-mediated therapy. Blood Cells Mol Dis. 2001;27:924–33.

    Article  PubMed  CAS  Google Scholar 

  12. Zhao X, Liu L, Wang FK, Zhao DP, Dai XM, Han XS. Coculture of vascular endothelial cells and adipose-derived stem cells as a source for bone engineering. Ann Plast Surg. 2012;69:91–8.

    Article  PubMed  CAS  Google Scholar 

  13. Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr Cartil. 2005;13:845–53.

    Article  PubMed  Google Scholar 

  14. Im GI, Lee JH. Repair of osteochondral defects with adipose stem cells and a dual growth factor-releasing scaffold in rabbits. J Biomed Mater Res B Appl Biomater. 2010;95:552–60.

    Google Scholar 

  15. Im GI, Kim HJ. Electroporation-mediated gene transfer of SOX trio to enhance chondrogenesis in adipose stem cells. Osteoarthr Cartil. 2011;19:449–57.

    Article  PubMed  Google Scholar 

  16. Kim YJ, Kim HJ, Im GI. PTHrP promotes chondrogenesis and suppresses hypertrophy from both bone marrow-derived and adipose tissue-derived MSCs. Biochem Biophys Res Commun. 2008;373:104–8.

    Article  PubMed  CAS  Google Scholar 

  17. Kim HJ, Im GI. Chondrogenic differentiation of adipose tissue-derived mesenchymal stem cells: greater doses of growth factor are necessary. J Orthop Res. 2009;27:612–9.

    Article  PubMed  CAS  Google Scholar 

  18. Kim HJ, Im GI. The effects of ERK1/2 inhibitor on the chondrogenesis of bone marrow- and adipose tissue-derived multipotent mesenchymal stromal cells. Tissue Eng Part A. 2010;16:851–60.

    Article  PubMed  CAS  Google Scholar 

  19. Ko JY, Kim KI, Park S, Im GI. In vitro chondrogenesis and in vivo repair of osteochondral defect with human induced pluripotent stem cells. Biomaterials. 2014;35:3571–81.

    Article  PubMed  CAS  Google Scholar 

  20. Lee JM, Kim BS, Lee H, Im GI. In vivo tracking of mesechymal stem cells using fluorescent nanoparticles in an osteochondral repair model. Mol Ther. 2012;20:1434–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Liau MT, Amini F, Ramasamy TS. The therapeutic potential of stem cells and progenitor cells for the treatment of parkinson’s disease. Tissue Eng Regen Med. 2016;13:455–64.

    Article  CAS  Google Scholar 

  22. Yun JW, Ahn JB, Kwon E, Ahn JH, Park HW, Heo H, et al. Behavior, PET and histology in novel regimen of MPTP marmoset model of parkinson’s disease for long-term stem cell therapy. Tissue Eng Regen Med. 2016;13:100–9.

    Article  CAS  Google Scholar 

  23. Amaratunga A, Khoury P, Wang L, Williams L, Tuch BE. Porcine pancreatic icosapeptide as a marker of graft survival and rejection in xenotransplantation. Xenotransplantation. 2003;10:622–7.

    Article  PubMed  Google Scholar 

  24. Emborg ME, Zhang Z, Joers V, Brunner K, Bondarenko V, Ohshima S, et al. Intracerebral transplantation of differentiated human embryonic stem cells to hemiparkinsonian monkeys. Cell Transpl. 2013;22:831–8.

    Article  Google Scholar 

  25. Little CB, Smith MM, Cake MA, Read RA, Murphy MJ, Barry FP. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in sheep and goats. Osteoarthr Cartil. 2010;18:S80–92.

    Article  PubMed  Google Scholar 

  26. Wilke HJ, Kettler A, Claes LE. Are sheep spines a valid biomechanical model for human spines? Spine. 1997;22:2365–74.

    Article  PubMed  CAS  Google Scholar 

  27. Armstrong SJ, Read RA, Ghosh P, Wilson DM. Moderate exercise exacerbates the osteoarthritic lesions produced in cartilage by meniscectomy: a morphological study. Osteoarthr Cartil. 1993;1:89–96.

    Article  PubMed  CAS  Google Scholar 

  28. Ghosh P, Burkhardt D, Read R, Bellenger C. Recent advances in animal models for evaluating chondroprotective drugs. J Rheumatol Suppl. 1991;27:143–6.

    PubMed  CAS  Google Scholar 

  29. Ghosh P, Sutherland J, Bellenger C, Read R, Darvodelsky A. The influence of weight-bearing exercise on articular cartilage of meniscectomized joints. An experimental study in sheep. Clin Orthop Relat Res. 1990;252:101–13.

    Google Scholar 

  30. Rørvik AM, Teige J. Unstable stifles without clinical or radiographic osteoarthritis in young goats: an experimental study. Acta Vet Scand. 1996;37:265–72.

    PubMed  Google Scholar 

  31. Dragoo JL, Samimi B, Zhu M, Hame SL, Thomas BJ, Lieberman JR, et al. Tissue engineered cartilage and bone using stem cells from human infrapatellar fat pads. J Bone Jt Surg Br. 2003;85:740–7.

    Article  CAS  Google Scholar 

  32. Bylski-Austrow DI, Malumed J, Meade T, Grood ES. Knee joint contact pressure decreases after chronic meniscectomy relative to the acutely meniscectomized joint: a mechanical study in the goat. J Orthop Res. 1993;11:796–804.

    Article  PubMed  CAS  Google Scholar 

  33. Ho C, Cervilla V, Kjellin I, Haghigi P, Amiel D, Trudell D, et al. Magnetic resonance imaging in assessing cartilage changes in experimental osteoarthrosis of the knee. Investig Radiol. 1992;27:84–90.

    Article  CAS  Google Scholar 

  34. Laurent D, O’Byrne E, Wasvary J, Pellas TC. In vivo MRI of cartilage pathogenesis in surgical models of osteoarthritis. Skelet Radiol. 2006;35:555–64.

    Article  Google Scholar 

  35. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48:3464–74.

    Article  PubMed  Google Scholar 

  36. Saw KY, Hussin P, Loke SC, Azam M, Chen HC, Tay YG, et al. Articular cartilage regeneration with autologous marrow aspirate and hyaluronic acid: an experimental study in a goat model. Arthroscopy. 2009;25:1391–400.

    Article  PubMed  Google Scholar 

  37. ter Huurne M, Schelbergen R, Blattes R, Blom A, de Munter W, Grevers LC, et al. Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis. Arthritis Rheum. 2012;64:3604–13.

    Article  PubMed  CAS  Google Scholar 

  38. Toghraie F, Razmkhah M, Gholipour MA, Faghih Z, Chenari N, Torabi Nezhad S, et al. Scaffold-free adipose-derived stem cells (ASCs) improve experimentally induced osteoarthritis in rabbits. Arch Iran Med. 2012;15:495–9.

    PubMed  Google Scholar 

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Acknowledgements

This study was supported by a grant of the Korea Healthcare technology R&D project, Ministry for Health & Welfare Affairs, Republic of Korea (HI14C0310). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Orthopedics, Dongguk University Ilsan Hospital, 814 Siksa-Dong, Goyang, 410-773, Republic of Korea

    Ji-Yun Ko, Jimin Lee & Gun-Il Im

  2. Research and Development Institute, MCTT Inc., Seoul, Republic of Korea

    Jungsun Lee

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  1. Ji-Yun Ko
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  2. Jungsun Lee
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Correspondence to Gun-Il Im.

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Ethical Statement

This study was approved by the Animal Research and Care Committee of Research and Development institution (MCTTIACUC ASP-15-001).

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Ko, JY., Lee, J., Lee, J. et al. Intra-articular Xenotransplantation of Adipose-Derived Stromal Cells to Treat Osteoarthritis in a Goat Model. Tissue Eng Regen Med 14, 65–71 (2017). https://doi.org/10.1007/s13770-016-0010-5

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  • DOI: https://doi.org/10.1007/s13770-016-0010-5

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